Public health genomics, nutrition and well-being:...the future

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1 ILSI PRAGUE October 2011 Public health genomics, nutrition and well-being:...the future Michael Fenech

2 THE NUTRIGENOMICS & DNA DAMAGE DIAGNOSTICS TEAM CSIRO C. Salisbury P. Thomas J. Crott V. Dhillon M. Hor T. Almond Jing Wu C. Bull N. O Callaghan W. Leifert G. Patten B. Benassi S. Beetstra FUNDING Kellogs Pty Ltd, MLA Blackmore s, Nutrilite/Amway NHMRC, CancerCouncil SA, NIH/NIAID EUCancerRisk Bio-markers Program DPI-Victoria Thank you Coordinating Group: Michael Fenech (Australia) Chairman Stefano Bonassi (Italy) Wushou Chang (Taiwan) Nina Holland (USA) Errol Zeiger (USA) Micheline Kirsch-Volders (Belgium) HUMN International Collaborative Project on Micronucleus frequency in human populations Founded Toulouse 1997 Acknowledgements 40 labs 16 countries >12,000 subjects >70,000 person years

3 It is always advisable to perceive clearly our ignorance. -Charles Darwin For a scientist, it is a unique experience to live through a period in which his/her field of endeavour comes to bloom to be witness to those rare moments when the dawn of understanding finally descends upon what appeared to be confusion only a while ago to listen to the sound of darkness crumbling. - George E. Palade

4 Italy Germany USA Poland Mexico Ecquador Bhutan Chad Egypt Dietary patterns & 1 week s food

5 FEEDING MORE & BETTER WITH LESS WHICH FOODS ARE THE MOST NUTRIENT DENSE? WHICH OF THESE ARE EASIEST TO GROW SUSTAINABLY? WHICH OF THESE HAVE THE LEAST IMPACT ON THE PLANET? WHICH OF THESE CAN BE EFFICIENTLY STORED? WHICH IS THE MINIMUM SET OF THESE FOODS TO MEET NUTRITIONAL REQUIREMENTS?

6 NUTRIENT DENSITY VS CLIMATE IMPACT OF BEVERAGES Smedman A et al 2010 Food & Nutrition Research 54: 5170 NNR = Nordic Nutrition Recommendations; Nutrient density=percentage of NNR in 100 g of product Number of nutrients]5% of NNR/21;. GHG = Greenhouse gas emissions

7 Folate content of vegetables (DFE µg per 100g)* *Data from USDA National Nutrient data base. DFE = dietary folate equivalent. DFE values are shown in brackets. High. Folate (HF) Vegetables Pulses Red Kidney beans (130) Mung beans (60) Chickpeas (171) Leafy or cruciferous vegetables Low Folate (LF) Vegetables Roots or Tubers Fruit Vegetables Broccoli (93) Onions (16) Tomato (15) Brussel sprouts (60) Potato (22) Pumpkin (9) Cabbage (43) Turnip (9) Cucumber (6) Lentils (180) Endive (142) Parsnip (57) Capsicum (11) Peas (59) Spinach (146) Swede (21) Eggplant (14) Lima beans (50) Lettuce (73) Carrot (14) Olives (0) Mean (108) Mean (93) Mean (23) Mean (10) Mean (100) Mean (16) Eating the wrong vegetables could lead to folate deficiency Folate RDA 400μg requires eating: 2.5Kg LF veg/d or 0.4Kg HF veg/d

8 The responsible and effective translation of genomebased knowledge for the benefit of population health. (Bellagio workshop, April 2005)

9 Public health in an era of genome-based and personalised medicine (...and nutrition/life-style) A strong consensus had emerged around certain principles which have grown out of the practice of public health genomics: The explicit rejection of genetic exceptionalism An emphasis upon the importance of translation supported by a strong evidence base Understanding the limits of personalised medicine

10 NUTRIGENOMICS Kussmann et al Nature Outlook 2010 DIET ENVIRONMENT LIFE-STYLE GENETICS EPIGENETICS TRANSCRIPTOMICS & PROTEOMICS METABOLOMICS & GENOMICS DNA METHYLATED DNA HISTONES, mirna RNA, PROTEINS METABOLITES & GENOME STABILITY THE BLUEPRINT WHAT HAS BEEN PROGRAMMED WHAT APPEARS TO HAPPEN WHAT HAS HAPPENED

11 NUTRIGENETICS Kussmann et al Nature Outlook 2010 ETICS & OMICS FOR PERSONALISED NUTRITION GENETICS EPIGENETICS TRANSCRIPTOMICS & PROTEOMICS METABOLOMICS & GENOMICS PERSONALISED NUTRITIONAL INTERVENTION TO UNDERSTAND PREDISPOSITION TO UNDERSTAND PROGRAMMING TO MEASURE MOLECULAR RESPONSE TO SHOW EFFICACY & SAFETY

12 Creating the Knowledge Base for Micronutrient Research in the Nutrigenomics Era The Micronutrient Genomics Project Operational Pipeline Infrastructure component Micronutrient Expert Groups Identify functional genetic variations Identify pathways & interactions Link to databases Create biological networks Bioinformatics Team Perform in vitro & mechanistic studies Micronutrient Genomics Portal Selection of relevant genetic variations Research component Link to omics data & results Research Collaborations Perform human intervention studies Link to nutritional phenotype database Establish relationships between genetic variations, micronutrients and optimal health Van Ommen et al. Genes Nutr ;5(4):

13 EFFECTS OF COMMON SNPs & MICRONUTRIENT CONCENTRATION ON... DRAFT MGP ROADMAP 2011 & BEYOND STAGE 1 EURRECA STAGE 2 COMPLETE GENE LISTS FOR KEY VITAMINS, MINERALS, PHYTONUTRIENTS IDENTIFY COMMON SNPs FOR EACH GENE (>=10% ALLEL FREQ) WITH STRONG FUNCTIONAL EFFECTS ON... STAGE 3 BUILD METABOLIC PATHWAYS & MATHEMATICAL MODELS TO PREDICT DIETARY REQUIREMENTS FOR DIFFERENT GENOTYPES STAGE 6 STAGE 7 ENZYME ACTIVITY BINDING AFFINITY DEFINE/DEVELOP APPROPRIATE IN VITRO /IN VIVO MODELS TEST PREDICTIONS IN APPROPRIATE IN VITRO/IN VIVO MODELS BIOMARKERS FOR VALIDATION OF PERSONALISED NUTRITION ADVICE STAGE 4 TISSUE NUTRIENT & METABOLITE CONCENTRATION GENOME STABILITY EPIGENOME GENE EXPRESSION STAGE 5 IMPROVE KNOWLEDGE ON APPROPRIATE BIOMARKERS OF ADEQUACY AND OPTIMAL HEALTH FOR EACH MICRONUTRIENT BOND HEALTH & DISEASE OUTCOMES

14 CROSS-SPECIES IN VIVO TRANSFER OF DNA & mirna VIA FOODS...ARE WE INDEED BECOMING GENETICALLY WHAT WE EAT? Rice mirna Ingestion Absorption Reduced Expression LDL receptor adapter protein 1 Increased LDL in blood Marine bacteria Zobellia In Nori Ingestion absorption Genetic transfer of Zobellia CAZ genes to Bacteroides Improved algal carbohydrate digestion via acquired agarases & porphyranases

15 NUT B [1] NUT B [2] NUT B [3] NUT C [1] NUT C [2] NUT C [3] NUT D [1] NUT D [2] NUT D [3] NUT E [1] NUT E [2] NUT E [3] NUTRIENT ARRAYS THE ROSETTA STONE FOR UNLOCKING PERSONALISED NUTRITION FOR GENOME MAINTENANCE NUT A [1] NUT A [2] NUT A [3] NUT B [1] NUT B [2] NUT B [3] NUT C [1] NUT C [2] NUT C [3] NUT D [1] NUT D [2] NUT D [3] IDENTIFY COMBINATIONS THAT OPTIMISE GENOME STABILITY AND CELL GROWTH Fenech M, Genome Integrity 20101: 11-15

16 A NUCLEOCENTRIC VIEW OF AGEING FROM WOMB TO TOMB The ageing genome and epigenome: damaged beyond repair? Is genomic damage reversible? Sinclair & Oberdoerffer, Ageing Res Rev July ; 8(3):

17 DNA DAMAGE BIOMARKERS LYMPHOCYTE CBMN ASSAY CHROMOSOME ABBS. RBC MN ASSAY COMET ASSAY TELOMERE LENGTH MITOCHONDRIAL DNA DELETION DNA OXIDATION DNA METHYLATION

18 DNA damage increases with age...or. poor choices of nutrition, life-style, physical and socio-psychological environments? MN per 1000 BN cells What is the threshold of DNA damage we should allow? Can we design exposomes that enable us to stay below this threshold? AGE (years) Fenech et al. 2000

19 Vitamin E Calcium Folate Retinol Nicotinic acid Riboflavin Pantothenic acid Biotin % variation in MN freq MICRONUTRIENTS AND GENOME DAMAGE RESULTS OF ANALYSIS OF FOOD FREQUENCY QUESTIONNAIRE AND GENOME DAMAGE DATABASE % variation in genome damage with increased intake relative to lowest tertile of intake * P < * * * * * * -Carotene * * * * * mid-tertile highest tertile Fenech et al. Carcinogenesis (2005)

20 PROPOSED ROAD-MAP TO DETERMINE DRVs FOR DNA DAMAGE PREVENTION NUTRITION VARIABLES SINGLE MICRONUTRIENT MICRONUTRIENT COMBINATION FUNCTIONAL FOOD FOOD GROUP DIETARY PATTERN STUDY DESIGN IN VITRO MODELS IN VIVO CROSS- SECTIONAL STUDIES PLACEB0- CONTROLLED TRIALS OUTCOME MEASURES PRIMARY DNA DAMAGE BIOMARKERS: MICRONUCLEUS CYTOME ASSAYS COMET ASSAY DNA OXIDATION DNA METHYLATION TELOMERE LENGTH mtdna DELETION SECONDARY TISSUE MICRONUTRIENT CONCENTRATION DRVs FOR GENOME STABILITY DATABASES ON VITAMIN & MINERAL REQUIREMENTS FOR GENOME STABILITY IN DIVERSE GENETIC BACKGROUNDS AT THE VARIOUS LIFE-STAGES Fenech M (2010) DRVs for Prevention of Genome Damage. Am. J. Clin. Nutr. 91: 1438S 1454S

21 LIFE-STYLE IS ALSO AN IMPORTANT DETERMINANT OF CHROMOSOMAL DNA DAMAGE LIFE-STYLE HPI INDEX Huang et al Preventive Medicine 48 (2009)

22 LONGER TELOMERES SHORTER FOLATE VITAMIN E VITAMIN D Ω3-FATTY ACIDS CEREAL FIBRE MULTIVITAMIN USE CURRENT limited KNOWLEDGE PUFA OXIDATIVE STRESS OBESITY PSYCHOLOGICAL STRESS PROCESSED MEAT HOMOCYSTEINE Int J Obes (Lond) Aug;34(8):1345-8; Am J Clin Nutr May;91(5): Rejuvenation Res Oct;12(5): ; Rejuvenation Res Jun;12(3): J Nutr Jul;139(7):1273-8; Am J Clin Nutr Jun;89(6): Am J Clin Nutr Nov;86(5):

23 Correlations 2010 May 25;5(5):e10826

24 Which diets and life-styles re-activate telomerase?

25 Telomere length (kb) High protein (TWD) or high carbohydrate (HC) weight-loss diets reverse telomere shortening in rectum in over-weight men completers protein TWD HC CHO O Callaghan, Clifton, Noakes, Fenech. Rejuvenation Res rotein weeks on diet CHO 2 way ANOVA P<0.0001

26 Lifestyle modifications included: Low fat (10% of calories from fat), whole foods, plant-based diet high in fruits, vegetables, unrefined grains, legumes, and low in refined carbohydrates; Moderate aerobic exercise (walking 30 min/day, 6 days/week); Stress management (gentle yoga-based stretching, breathing, meditation, imagery, and progressive relaxation techniques 60 min/day, 6 days/week), and a 1-h group support session once per week. Supplementation with soy (one daily serving of tofu plus 58 g of a fortified soy protein powdered beverage), fish oil (3 g daily), vitamin E(100 IU daily), selenium (200 μg daily), and vitamin C (2 g daily).

27 Can meditation slow rate of cellular aging? cognitive stress, mindfulness, and telomeres Epel E et al, Ann N Y Acad Sci. 2009; 1172: Jacobs TL et al J Neuroendocrinology 2011; 36(5):664-81

28 LOVE* PURPOSE EXERCISE INCREASING AWARENESS THAT WE ARE 3-D BEINGS ONENESS CREATIVITY SLEEP WISDOM FREE WILL NUTRITION BODY MIND *lack of fear/neuroticism? SOUL

29 We are at the threshold of a new era in which harm to the genome can be efficiently diagnosed and prevented. A person s DNA damage profile should become a routine biomarker of health status. Prevention of DNA damage will soon achieve its rightful place as one of the most important objectives of global health strategies. M. Fenech 2010 INCONN Brazil

30 NUTRI- GENOMICS TOXICO- GENOMICS GENOME HEALTH STATUS OF INDIVIDUALS POPULATIONS PSYCHO- GENOMICS LIFESTYLE GENOMICS

31 Personalised diets and life-styles for morbidity compression or life extension? Which is the most cost-effective model? Morbidity onset Death COST Present life-span & morbidity $$ Birth Morbidity onset Death Life extension with morbidity extension $$$$ Birth Morbidity compression but no life extension Morbidity onset Death $ Birth Life extension & morbidity compression Morbidity onset Death $$ Birth

32 NUTRITION 2020 & BEYOND PERSONALISED ADVICE BASED ON AN ALMOST COMPLETE UNDERSTANDING OF NUTRITIONAL & LIFE-STYLE REQUIREMENTS TAILORED TO GENOTYPE, EPIGENOTYPE & LIFE-STAGE IMPROVED: METABOLIC FLEXIBILITY, GENOME INTEGRITY, REGENERATIVE POTENTIAL MORBIDITY COMPRESSION BIOMARKERS SPECIFIC TO FUNCTIONALITY

33 PERSONALISED NUTRITIONAL COUNTERMEASURES FOR MICROGRAVITY & COSMIC RADIATION-INDUCED DNA DAMAGE FOR SPACE TRAVELLERS AND EXTRA-TERRESTRIAL COLONIES

34 A NEW HIPPOCRATIC OATH FOR OUR PIONEER DOCTORS OF HEALTH? I swear to fulfill, to the best of my ability and judgment, this covenant: I shall endeavour to use the knowledge given to me to help my fellow beings to stay as healthy as possible at the genome, cellular, organ, system and psychological level so that they will not require to be cured from a preventable disease. I shall appropriately use the best validated diagnostics available so I can determine with certainty the extent to which my fellow human has drifted from optimal health and the causes of such harm. I shall use holistic methods including nutrition, life-style, environmental and sociopsychological approaches that are best suited to return my fellow human to optimal well-being sustainably, within their means, so that they will not require my services to provide a cure for a preventable disease. At the community level, I shall contribute to create ecologically viable, enjoyable, stimulating environments and caring but challenging societies, allowing equal opportunity for realising one s purpose and creative potential whilst securing optimal health to do so.

35 BETTER ENVIRONMENTS...BETTER WORK-LIFE BALANCE

36 REGENERATION MINDSCAPE A CONVERGENT PERSPECTIVE, COMBINING EVOLUTIONARY BIOLOGY, GENOMICS, ENVIRONMENTAL NEUROBIOLOGY AND CLINICAL MEDICINE TO UNDERSTAND LIFE, MIND, CONSCIOUSINESS AND HAPPINESS LIFESCAPE MINDSCAPE Niculescu, Schork, Salomon, Journal of Affective Disorders 123 (2010) 1 8

37 PERSONALISED NUTRIOMES FOR GENOME STABILITY, DIFFERENTIATION & GROWTH OF STEM We now live in an era when stem cells are taken out of the body and expanded in vitro before being returned to the body Stem cell or ips cell cytogenetic abnormalities constitute a roadblock to regenerative therapies because they increase the rate of senescence and the risk of oncogenic transformation. Determining the optimal nutriome in culture medium that prevent chromosomal instability for each stem cell or ips culture is therefore important not only to predict in vivo requirements but also in vitro nutrient requirements for DNA damage prevention THE HUMAN BODY SHOP

38 PERSONALISED CANCER GROWTH CONTROL IN CANCER SURVIVORS BY DIETARY RESTRICTION? DISCOVERY OF ACQUIRED GENETIC MUTATIONS THAT MAKE A CANCER DEPENDENT ON A SPECIFIC NUTRIENT VERIFICATION OF CANCER GROWTH CONTROL BY IN VITRO RESTRICTION TESTS DESIGN DIETARY PATTERNS TO RESTRICT NUTRIENT IN VIVO

39 IS IT POSSIBLE TO INCREASE THE HEALTHY LIFE-SPAN AND COMPRESS MORBIDITY? Fries JF et al (2011) J Aging Res Which dietary and life-style factors compress morbidity? Progression of disability in Runner sclub and Community Control groups over 21 years from an average age of 58 Which biomarkers predict morbidity compression? Can we design personalised functional foods for morbidity compression?